Exercise continues to be an important behavior in the regulation of body weight. On the other hand, the short-term and long-term importance and mechanisms of how exercise regulates body weight and energy balance are not thoroughly understood. As a consequence, a trans-disciplinary and translational approach to this topic may be needed to provide new insights into gaps in the scientific study of exercise and weight regulation, and to forge new frontiers for research initiatives in this area. What Don't We Know About Exercise and Body Weight Regulation: A Trans-Disciplinary and Translational Perspective reviews perspectives of gaps in the scientific literature, and details how the combined use of both animal, human, and intervention/community models can inform new perspectives to advance the research in this very important public health area.